Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy

被引：56

作者：

Zammataro, Luca ^{[1
]}

Lopez, Salvatore ^{[1
,2
]}

Bellone, Stefania ^{[1
]}

Pettinella, Francesca ^{[1
]}

Bonazzoli, Elena ^{[1
]}

Perrone, Emanuele ^{[1
,3
]}

Zhao, Siming ^{[4
]}

Menderes, Gulden ^{[1
]}

Altwerger, Gary ^{[1
]}

Han, Chanhee ^{[1
]}

Zeybek, Burak ^{[1
]}

Bianchi, Anna ^{[1
]}

Manzano, Aranzazu ^{[1
]}

Manara, Paola ^{[1
]}

Cocco, Emiliano ^{[5
]}

Buza, Natalia ^{[6
]}

Hui, Pei ^{[6
]}

Wong, Serena ^{[6
]}

Ravaggi, Antonella ^{[7
]}

Bignotti, Eliana ^{[7
]}

Romani, Chiara ^{[7
]}

Todeschini, Paola ^{[7
]}

Zanotti, Laura ^{[7
]}

Odicino, Franco ^{[7
]}

Pecorelli, Sergio ^{[7
]}

Donzelli, Carla ^{[8
]}

Ardighieri, Laura ^{[8
]}

Angioli, Roberto ^{[9
]}

Raspagliesi, Francesco ^{[10
]}

Scambia, Giovanni ^{[11
]}

Choi, Jungmin ^{[12
,13
]}

Dong, Weilai ^{[12
]}

Bilguvar, Kaya ^{[14
]}

Alexandrov, Ludmil B. ^{[15
]}

Silasi, Dan-Arin ^{[1
]}

Huang, Gloria S. ^{[1
]}

Ratner, Elena ^{[1
]}

Azodi, Masoud ^{[1
]}

Schwartz, Peter E. ^{[1
]}

Pirazzoli, Valentina ^{[1
,16
,17
]}

Stiegler, Amy L. ^{[1
]}

Boggon, Titus J. ^{[1
]}

Lifton, Richard P. ^{[1
]}

Schlessinger, Joseph ^{[1
,17
]}

Santin, Alessandro D. ^{[1
]}

机构：

[1] Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT 06510 USA

[2] Magna Graecia Univ Catanzaro, Dept Expt & Clin Med, I-88100 Catanzaro, Italy

[3] Univ Cattolica Sacro Cuore, Inst Obstet & Gynecol, I-00168 Rome, Italy

[4] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[5] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[6] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA

[7] Univ Brescia, Dept Obstet & Gynecol, Angelo Nocivelli Inst Mol Med, I-25100 Brescia, Italy

[8] Univ Brescia, Dept Pathol, I-25100 Brescia, Italy

[9] Univ Campus Biomedico Roma, Dept Gynecol & Obstet, I-00128 Rome, Italy

[10] Fdn Ist Ricovero Cura, Dept Gynecol Oncol, I-20133 Milan, Italy

[11] Fdn Policlin Univ A Gemelli, Ist Ricovero Cura Carattere Scientifico, Dept Woman & Child Hlth Sci & Publ Hlth, Unit Gynecol Oncol, I-00168 Rome, Italy

[12] Rockefeller Univ, Dept Genet, New York, NY 10065 USA

[13] Korea Univ, Coll Med, Dept Biomed Sci, Seoul 02841, South Korea

[14] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[15] Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[16] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06510 USA

[17] Yale Univ, Dept Pharmacol, Sch Med, New Haven, CT 06520 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2019年 / 116卷 / 45期

关键词：

cervical cancer; PIK3CA; HER2/neu; neratinib; copanlisib; CANCER; EXPRESSION; DIAGNOSIS; INSIGHTS; COMPLEX; GROWTH; SMAD4;

D O I：

10.1073/pnas.1911385116

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirustype-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TON motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNV5), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNV5 as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring ERBB2 (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models (P = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.

引用

页码：22730 / 22736

页数：7

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